Breast cancer incidence and mortality remains a major health problem worldwide. We have developed a novel vitamin E analog referred to as alpha-TEA that inhibits growth of human cancer cells and does not exhibit toxicities to normal cells and tissues. We hypothesize that alpha-TEA will be effective as a chemotherapeutic agent for breast cancer. Goals are to investigate the ability of alpha-TEA to: (i) enhance survival of NU/NU mice transplanted with human MDA-MB-435 breast cancer cells, (ii) reduce lung metastases following treatment after removal of primary tumors, and (iii) act cooperatively in combination with doxorubicin in reducing tumor burden and metastasis. Additionally, we will study alpha-TEA's mechanisms of action as an antitumor agent. Proposed studies are supported by data showing alpha-TEA to: (i) significantly reduce tumor burden and metastases in a human MDA-MB-435 breast cancer xenograft model, (ii) sensitize MDA-MB-435 cells to low dose doxorubicin- induced apoptosis in cell culture, and (iii) induce tumor cell death by blocking cell survival signaling and by restoring pro-apoptotic signaling pathways. 3 key events in alpha-TEA-mediated apoptosis in human breast cancer cells are: blockage of prosurvival HER2/ AKT/FLIP signaling; restoration of TRAIL7DR5 and Fas/Fas Ligand apoptotic signaling pathways; and signaling of apoptosis via both mitochondria-dependent and -independent pathways. Proposed studies are highly significant in that they are focused on pre-clinical development of a promising, new therapeutic agent for treatment of breast cancer. Proposed mechanistic studies have a high potential for identifying and characterizing dysregulated signaling pathways/events that are modifiable and therefore may serve as important molecular targets for treatment of breast cancer.